Opioids such as morphine are the most effective treatment for pain. Unfortunately, this opioid analgesia is limited by the development of tolerance with repeated administration. Cannabinoids also have been shown to have analgesic effects, but this antinociception is much more mild than that produced by opioids. The combined administration of opioids and cannabinoids has the potential to enhance the analgesic effects of both drug classes and reduce the development of tolerance to opioids. Our preliminary data and published reports by others show that alternating opioid and cannabinoid treatment can enhance the analgesic effects of both opioids and cannabinoids. Our data show that repeated injections of the cannabinoid HU-210 into a brain structure called the periaqueductal gray (PAG) enhances the analgesic effect of a morphine injection into the PAG on a subsequent day. This finding suggests that the ability of cannabinoids to enhance morphine antinociception is mediated by the PAG. The first objective of this grant proposal (Aim 1) is to test the hypothesis that the antinociceptive effect of microinjecting a cannabinoid into the PAG will be enhanced in morphine tolerant rats. In addition, these PAG mediated effects will be compared to cannabinoid/opioid interactions in the rostral ventromedial medulla (RVM)-the primary output target for neurons in the PAG. Rats will be made tolerant to either morphine or HU-210 and then tested for enhanced analgesia to injection of either HU-210 or morphine into the PAG or RVM. The second objective (Aim 2) is to determine how this interaction between cannabinoids and opioids occurs. In particular, anatomical and electrophysiological techniques will be used to determine whether cannabinoids and opioids interact on the same or different neurons in the PAG. These studies will provide insights into the mechanisms underlying cannabinoid/opioid interactions. An understanding of these mechanisms will allow the development of pain treatments that both reduce tolerance to opioids and enhance the analgesic effects of opioids and cannabinoids. Thus, these simple, but innovative experiments could have a significant impact on improving the treatment for pain. PUBLIC HEALTH RELEVANCE: Persistent pain is a serious medical problem. Although the effectiveness of opioids to treat severe pain diminishes with repeated administration, prior treatment with a cannabinoid appears to enhance the analgesic effects of morphine. The proposed studies will examine possible mechanisms for this potentiation between opioids and cannabinoids so better pain treatments can be developed.